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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.


Last Update: August 30, 2022.



Thalidomide and its analogues lenalidomide and pomalidomide are immunomodulatory and antineoplastic agents that are used in the therapy of multiple myeloma. These three agents are associated with a low rate of serum aminotransferase elevations during therapy and have been implicated in causing rare instances of clinically apparent liver injury which can be severe.


Thalidomide (tha lid' oh mide) is a glutamic acid derivative that was introduced in Europe as a sedative in the late 1950s and subsequently withdrawn in 1961 when it was shown to be teratogenic, causing severe infant limb defects (phocomelia) when given to pregnant women. Several decades later, thalidomide was found to have potent activity in erythema nodosum leprosum, and subsequent studies found it beneficial in several autoimmune conditions and cancers. Thalidomide has immunomodulatory, antiinflammatory, antiangiogenic and anticancer properties that underlie its effects in inflammatory and malignant diseases. Thalidomide was approved for therapy of erythema nodosum leprosum (ENL) in the United States in 1998 and was subsequently approved for use in multiple myeloma (in combination with dexamethasone) in 2006. Lenalidomide (len" a lid' oh mide) and pomalidomide ae thalidomide derivatives that were found to be more potent as antineoplastic agents, and were subsequently approved for use in selected myelodysplastic syndromes and for multiple myeloma (combined with dexamethasone). Thalidomide has also been used on an experimental basis for graft vs host disease, Kaposi sarcoma, AIDS associated wasting syndrome and several forms of autoimmune disease. Thalidomide is available in capsules of 50, 100, 150 and 200 mg under the brand name Thalomid. The recommended dose varies by indication, and its use is restricted because of their proven teratogenicity. Side effects of thalidomide are common and include sedation, dizziness, orthostatic hypotension, neutropenia, thrombocytopenia, peripheral neuropathy, and venous and arterial thromboembolism (for which reason it is usually given with anticoagulation). Rare but potentially severe adverse events include severe cutaneous reactions, seizures, tumor lysis syndrome and hypersensitivity reactions. Thalidomide is a known teratogen and cause of severe birth defects and is available only as a part of a strict Risk Evaluation and Mitigation Strategy (REMS), which requires physician training, patient fully informed consent, strict birth control measures, monitoring and reporting.


Serum enzyme elevations occur in 8% to 15% of patients taking thalidomide and are more frequent with higher doses. The enzyme abnormalities are usually mild and self-limited, and only rarely require drug discontinuation. In addition, both thalidomide and its derivatives, lenalidomide and pomalidomide, have been implicated in rare instances of clinically apparent, acute liver injury which can be severe and has led to deaths from acute liver failure. The onset of injury is typically within 1 to 8 weeks of starting therapy. The pattern of serum enzyme elevation at the time of presentation can be either hepatocellular or cholestatic; however, the injury tends to be cholestatic and can be prolonged. Immunoallergic and autoimmune features are not common. Several instances of acute liver injury associated with thalidomide therapy have occurred in patients with other apparent causes of liver disease or with preexisting chronic hepatitis B or C. If performed during the acute injury, liver biopsy shows hepatocellular necrosis and inflammatory cell infiltration, consistent with acute drug induced injury. In some instances there is bile duct injury and loss resulting in progressive cholestatic liver injury suggestive of vanishing bile duct syndrome. Thalidomide and its derivatives have also been implicated in causing an increased risk of graft-vs-host disease after autologous or allogeneic hematopoietic stem cell transplantation (HSCT). There appears to be cross reactivity to this complication among thalidomide and its two derivatives. Therapy usually requires discontinuation of the antineoplastic agent as well as treatment with high doses of corticosteroids and tacrolimus or sirolimus.

Reactivation of hepatitis B has been reported in patients receiving thalidomide, lenalidomide and pomalidomide, but generally only after HSCT. In studies of large numbers of patients treated for multiple myeloma with these agents, the major risk factor for reactivation was HSCT rather than the specific antineoplastic drugs being used. Indeed, lenalidomide therapy was associated with a reduced risk of reactivation in patients with HSCT (although dexamethasone, thalidomide and bortezomib were not), perhaps because of the typical immune enhancement caused by lenalidomide.

Likelihood score: B (well known but rare cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of thalidomide hepatotoxicity is not clear, but it may be related to its activity in reducing TNF-α production, a potent inflammatory cytokine that activates T cells and promotes inflammation, but is also necessary for normal liver regeneration. Several of the reported cases of hepatotoxicity have occurred in patients with underlying chronic liver disease (hepatitis B, C or nonalcoholic fatty liver), and another possibility is that thalidomide may worsen preexisting hepatic conditions.

Outcome and Management

The severity of thalidomide induced liver injury ranges from transient, asymptomatic elevations in serum enzymes to acute liver injury with jaundice to severe acute liver failure and death. The liver injury usually starts to resolve within a week of stopping the medication, but prolonged jaundice with bile duct injury and possible vanishing bile duct syndrome have also been reported. Rechallenge should be reserved for cases of mild liver injury in which the agent is considered very necessary and done with caution and careful monitoring. Nevertheless, instances of reinitiation of therapy without subsequent recurrence of liver injury have been reported.

Drug Class: Antineoplastic Agents, Miscellaneous

Other Related Drugs: Lenalidomide, Pomalidomide


Case 1. Acute hepatitis due to thalidomide.(1)

A 76 year old woman with multiple myeloma developed jaundice 5 weeks after starting thalidomide combined with warfarin and intermittent dexamethasone. She had no previous history of liver disease or risk factors for viral hepatitis. She did not drink alcohol. Her only other medications were metoprolol and furosemide for hypertension and insulin for diabetes. Routine liver tests had been normal in the past. Routine monitoring of serum enzymes demonstrated rises in ALT and AST after 4 weeks of treatment. Thalidomide was continued, and one week later she developed nausea, fatigue, abdominal discomfort and jaundice. On physical examination, she was jaundiced but had no fever, rash or signs of chronic liver disease. Laboratory tests showed bilirubin 5.6 mg/dL, ALT 2206 U/L, and international normalized ratio (INR) of greater than 15. She was admitted to the hospital for management and both thalidomide and the warfarin were stopped. Tests for hepatitis A, B and C were negative as were autoantibodies. Imaging of the liver showed evidence of diffuse fatty liver, but no masses or biliary obstruction. She was treated with fresh frozen plasma to correct the INR and underwent transjugular liver biopsy which was interpreted as compatible with acute drug induced liver injury superimposed upon an underlying nonalcoholic steatohepatitis. After thalidomide was stopped, she began to improve rapidly (Table). She was discharged after a week in the hospital and, when seen three months later, her liver tests were normal.

Key Points

Pattern:Hepatocellular (R value could not be determined)
Severity:3+ (jaundice and hospitalization)
Latency:4 to 5 weeks
Recovery:Complete within 30 days
Other medications:Furosemide, metoprolol, insulin, warfarin, dexamethasone

Laboratory Values

Time After
Time After
Alk P*
4 weeks218179
5 weeks0220523765.6INR >15, admission
1 day22502425Thalidomide stopped
4 days15001050
6 weeks12 days165865.5INR 1.1: Discharged
4 months3 monthsNormalNormalNormalOutpatient follow up
Normal Values <34 <35 <1.2

Some values estimated from Figure 1.


This woman developed jaundice within 5 weeks of starting an experimental regimen of cancer chemotherapy including thalidomide, warfarin and dexamethasone. Typical of thalidomide hepatotoxicity was the latency to onset (1 to 3 months), the hepatocellular pattern of injury (although no alkaline phosphatase values were provided in this case), the presence of an underlying liver disease, and the rapid improvement with stopping the medication.



Thalidomide – Thalidomid®

Lenalidomide – Revlimid®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Thalidomide 50-35-1 C13-H10-N2-O4 image 134971183 in the ncbi pubchem database
Lenalidomide 191732-72-6 C13-H13-N3-O3 image 135134887 in the ncbi pubchem database
Pomalidomide 19171-19-8 C13-H11-N3-O4 image 135089995 in the ncbi pubchem database


Hanje AJ, Shamp JL, Thomas FB, Meis GM. Thalidomide-induced severe hepatotoxicity. Pharmacotherapy. 2006;26:1018–22. [PubMed: 16803426]


References updated: 30 August 2022

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    (Japanese nationwide analysis of 5078 patients with multiple myeloma identified 760 with resolved hepatitis B [anti-HBc without HBsAg in serum] of whom 7.6% developed reactivation [7.9% at 2 and 14.1% at 5 years], multivariate analysis demonstrating higher rates in those undergoing autologous hematopoietic stem cell transplant [21%:odds ratio=11.6] and lower rates in those receiving lenalidomide [5.2%:odds ratio=0.5], but not thalidomide, bortezomib or dexamethasone).